Novel immonium salts

ABSTRACT

WHEREIN R and R1 are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene, -CH2-CH2-O-CH2-CH2- and   WHERE R4 is alkyl of 1 to 5 carbon atoms, R2 and R3 are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and phenyl and taken together are selected from the group consisting of alkylene of 3 to 5 carbon atoms and benzoalkylene of 7 to 10 carbon atoms, X is halogen and Y is selected from the group consisting of dilower alkylamino wherein the alkyl have 1 to 5 carbon atoms, morpholino, piperidino and 1-pyrrolidinyl.   Novel intermediates useful for organic synthesis which are immonium salts of the formula

United States Patent 1191 Viehe et al.

[ Mar. 25, 1975 1 NOVEL IMMONIUM SALTS [751 Inventors: Heinz G'tinter Viehe, Beersel;

Therese Van Vyvc, Kraninhcm; Zdenek .lanousek, Lcuven. all 01' Belgium |73| Assigncc: Roussel UCLAI", Paris, France [2).] lilull June 21, 1973 1211 Appl. No.: 372,17l

[30] Foreign Application Priority Data June 28, 1972 France 72.23349 1521 US. Cl 260/240 R, 424/251, 424/273,

260/246 B, 260/2475 R, 260/247.7 K,

260/2564 N, 260/268 H, 260/268 R,

511 Int. Cl C09b 23/00 158] Field of Search... 260/240 R, 567.6 R, 325.86, 260/247.5 R, 293.87, 293.7, 268 H, 268 R [56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,206,185 9/1970 United Kingdom 260/310 1,410,864 10/1964 France .,260/306.8 R, 260 H Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Hammond & Littell [57] ABSTRACT Novel intermediates useful for organic synthesis which are immonium salts of the formula wherein R and R,- are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene, CH CH OCH CH and 12 Claims, N0 Drawings NOVEL IMMONIUM SALTS STATE OF THE ART French Pat. No. 1,410,864 describes certain immonium salts useful as intermediates for dyes and British Pat. No. l.206,l85 describes immonium salts useful as intermediates for pyrazoles and pyrimidines but none of the compounds of the said patents are related to the compounds of formula I.

OBJECTS OF THE lNVENTlON THE lNV ENTION The novel immonium salts of the invention have the formula wherein R and R are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene,

and

where R is alkyl of l to carbon atoms, R and R are individually selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and phenyl and taken together are selected from the group consisting of alkylene of 3 to 5 carbon atoms and benzoalkylene of 7 to 10 carbon atoms, X is halogen and Y is selected from the group consisting of dilower alkylamino wherein the alkyl have 1 to 5 carbon atoms, morpholino, piperidino and l-pyrrolidinyl.

Among the preferred compounds of formula I are those wherein R and R, are alkyl of l to 5 carbon atoms such as methyl or ethyl, or phenyl substituted with a chlorine atom or taken together are alkylene of 2 to 6 carbon atoms and R and R are alkyl of l to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, isobutyl or tert.-butyl or taken together are benzoalkylcnc with l to 4 carbon atoms in the alkylcne such as wherein n is l to 3, preferably l or 2, R. is methyl. X is bromine or chlorine and Y is dialkylamino such as dimethylamino and diethylamino.

The process of the invention for the preparation of the immonium salts of formula l comprises reacting an immonium phosgene salt of the formula N x 9 II wherein X, R and R have the above definitions with an enamine of the formula III wherein R R and Y have the above definitions to obtain the corresponding immonium salt of formula I. The reaction is preferably effected in solution in an organic solvent such as methylene chloride or chloroform in substantially equimolar amounts at temperatures from 50 to l50C, preferably 0 to 50C and most preferably at room temperature. The compounds of formula I may' be recovered by evaporation of the solvent or by precipitation such as by addition to either in which they are insoluble.

The compounds of formula ll may be prepared by known processes [such as that described by Senning. Chem. Rev., Vol. 65 (1965), p. 388] by reacting a halogen X with a thiocarbamoyl halide of the formula The chlorides of N-methyl-N-benzyl-dichloromethyl immonium, N-morpholino-dichloromethyl imtnonium and N-methyl-N-pipcrazino dichloromethyl immonium may be prepared by reacting chlorine with the corresponding thiocarbamoyl chloride in asolven-t such as methylene chloride. N,N-dimethyl-dichloromethyl immonium chloride may be prepared by reacting chlorine with tetramethylthiuram disulfide [Viehe et al., Angewandte Chemie, International Ed, Vol. (197] J, p. 57344].

The enamincs of formula [I] may be prepared by standard methods ofproducing enamines such as reacting a secondary amine of the formula YH with a carbonyl derivative of the formula wherein Y, R: and R have the above definitions.

The novel process of the invention for the preparation of pyrazoles of the formulae T and f IVb wherein R, R,, R and R have the above definitions and R is selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and phenyl and isomers thereof when R is other than hydrogen comprises reacting a hydrazine of the formula verted into the free pyrazole by addition of a mineral base such as an aqueous solution of an alkali metal hydroxide. The pyrazole may be recovered by standard procedures such as evaporation of the solvent or by extraction and then evaporation of the solvent.

When R is hydrogen, the pyrazole is a mixture ofthe tautomers of formulae Wu and NI). When R is other than hydrogen, the isomers of formulae [Va and [Vb may be separated such as by chromatography.

The compounds of formula [Va and [Vb have interesting pharmacological properties, namely analgesic and anti-inflammatory activity and therefore are useful for the treatment of affections characterized by inflammation such as sciatic, rheumatism, arthrosis, muscular or articular pains, toothaches and migraines. Some of these compounds have been described in British Pat. No. 1145544 as analgesics and anti-inflammatory agents. R is preferably methyl. ethyl, isopropyl, n-butyl or tert.-butyl in formulae [Va and lVb.

The novel process of the invention for the preparation of pyrimidines of the formula wherein R, R R and R have the above definitions and R is selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and aryl of 6 to 10 carbon atoms comprises reacting an amidine of the formula VII

with a compound of formula I.

Preferably, the reaction is effected by progressively adding the product of formula I to a solution of the amidine of formula Vll in a solvent such as methylene chloride although the reaction may be effected without any solvent by heating a mixture of the 2 reactants. The reaction is preferably effected in the presence of a tcrtiary base such as triethylamine at 50 to [50C. The reaction when conducted in methylene chloride is effected at reflux preferably. After Completion of the reaction, the mixture is neutralized by addition of a mineral base such as an aqueous solution of sodium hydroxide or potassium hydroxide and recovering the pyrimidine in the usual fashion.

The pyrimidines of formula V have useful biological properties, particularly fungicidal activity making them useful in agriculture to combat plant diseases caused by, 'fungi. Some of the pyrimidines of formula V have been described as fungicidal agents in French Pat. No. 1,583,150. R is preferably methyl, ethyl, propyl, phenyl or naphthyl in formula V and VII.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it is to be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLES l to 9 The compounds reported in Table l were prepared by the following procedure: The phosgene-immonium salt of formula II was suspended in methylene chloride or chloroform and then a solution of a stoichiometric amount of the enamine of formula [[1 in methylene chloride or chloroform was added dropwise to the suspension stirred at room temperature. The stirring was continued until the phosgene immonium salt was all reacted as noted by the reaction mixture becoming a solution. About two-thirds of the solvent was evaporated and then an excess of ether was added to cause precipitation of the salt of formula I. The product was washed with pentane and then dried under reduced pressure.

TABLE 5 ComiTid Startim Materials Example *PfioSgene-mmomum Enamine of Reaction Product of formula I U.v, Spectra no, salt formula II formula III Solvent fill lax, in nm R R1 X R2 R3 Y cl 6 37s 7 (CH 0 (CH2)2 (:1 (CH r o cncl en en 3\/ 3 en N (D c). 3 cn n i A 8 e11 cs c1 n c c11 N\CH cr ct c Cl 3 H C CH3 3 gli i y H C en 3 9 CH en c1 -cn -c=c- -N' CH 01 3\/ 3 HC on N C1 c-cn c1 Cl The structures of the products of Examples 1 to 9 and the mixture was stirred for 15 nm. The correspondwere confirmed by hydrolysis of the products to form ing B-oxo amide in the aqueous phase was extracted the corresponding B-oxo-amides. l g of the product of with methylene chloride or chloroform and the solvent the examples was dissolved in 100 ml of chloroform or 35 was evaporated from the extracts. The residue was pumcthylene chloride and an excess of an aqueous saturified by distillation under reduced pressure and some rated sodium bicarbonate solution was added thereto of the B-oxo amides recovered are reported in Table ll.

TABLE II l Hydrolysis of; l

compound of B-oxo amide formula I of Example No. 5 Formula Characteristics l t 1 CH CH p 3 3 1 Boiling Point llO-l20C at 0.2 mm LR -vMa.X. at C\\O 1710, l6 0 cm 1* j \;o

H s 3 I j Boiling Point: 120C at l 2 0.05 mm Hg LR. -v Max. at i 29 O, 2O, 2790, 1710 and i i l 16 0 cm l \0 l I -Continued Hydrolysis of compound B-oxo amide formula I of Example No. Formula Characteristics CH CH Boiling Point 16o-17oc at 5 5 mm Ha I. Max. at

i 1710, 1640 cm CH CH i 3 v 6 N LR. Max. at 2 40 i C H 2740, 1730, 1640 cm' 1 6 c o i 1.. i H l 7 Boiling Point 130C at l 0.05 gm Hg ILR. Max. t 2 i \\o iguo9cg 28 O, 1710 and I l EXAMPLE The mixture consisted of 90% of isomer A and 10% of A solution of 0.032 moles of methylhydrazine in 50 ml of chloroform was added dropwise with stirring to a solution of 0.030 moles of the product of Example 1 in l00 ml of chloroform and the resulting mixture was refluxed (about 70C) for 14 hours. The hydrochloric acid formed was neutralized by addition of a concen trated aqueous solution of potassium hydroxide and the mixture was extracted with chloroform. The chloroform extract was evaporated to dryness and the residue was distilled under reduced pressure to recover the product coming off at 80 to 85C at 0.02 mm Hg. The product was a mixture of the pyrazoles of the formulae isomer B and could be separated by chromatography. RMN Spectroscopy in CDCig gave the following characteristics:

isomer A: 5 1.75 (4H.m); 2.45 (4H.m); 2.78

(6H5); 3.55 (3H.s). Isomer B: 8 1.70 (4H.m); 2.5 (4H.m); 2.65 (6H.s);

EXAMPLE 11 CH H i and 3 CH3 G isomer A isomer B Z P-Z 11 with a boiling point of 170C at 0.04 mm Hg. This RMN Spectrum was as follows: 9.3 (1H.br); 2.85 (6l-l.s); 2.6-1.4 (8H).

EXAMPLE 12 Using the procedure of Example 11, phenyl hydrazine was reacted with the product of Example 1 to obtain a mixture of pyrazole of the formulae CH C CH \1\/CH3 3 EXAMPLE 13 I 1.04 g of benzamidine and 2.5 ml of triethylamine were introduced into 100 ml of methylene chloride and then a solution of 2.7 g of the compound of Example 1 in 50 ml of methylene chloride was added dropwise thereto. The mixture was refluxed with stirring for 24 hours and was then neutralized with a potassium hydroxide solution. The aqueous phase was saturated with potassium carbonate and then was extracted with methylene chloride. The methylene chloride was eliminated by evaporation from the extract and the residue was distilled under reduced pressure to obtain the pyrimidine of the formula EXAMPLE 14 Using the procedure of Example 13, 0.7 g of the product of Example 5 was reacted with 0.52 g of benzamidine and 1.5 ml of triethylaminc to obtain the pyrimidinc of the formula distilling at C at 0.04 mm Hg. The product was purified by crystallization from benzene. The product had amass spectra of 301 (M") and IR spectrum 2940. 2860, 1600 and 1550 cm.

Various modification of the products and processes of the invention may be made without departing from the spirit or scope thereof and it should be inderstood that the invention is to be limited only as defined in the appended claims.

We claim:

1. lmmonium salts of the formula wherein R and R are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene, CH CH -OCH CH and 3 -CH2-CH2 All-CH -cH where R is alkyl of l to 5 carbon atoms, R and R are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and phenyl and taken together are selected from the group consisting of alkylene of 3 to 5 carbon atoms and benzoalkylene of 7 to 10 carbon atoms, X is halogen and Y is selected from the group consisting of dilower alkylamino wherein the alkyl have 1 to 5 carbon atoms, morpholino, piperidino and l-pyrrolidinyl.

2. The compounds of claim 1 wherein X is chlorine.

3. A compound of claim 2 wherein R and R are methyl, R and R together are (CH and Y is lpyrrolidinyl.

4. A compound of claim 2 wherein R and R together are and Y is l-pyrrolidinyl.

12. A process for the preparation of a compound of claim 1 comprising reacting a phosgene-immonium salt of the formula RK/g 69 wherein R, R and X have the definitions of claim 1 with an enamine of the formula wherein R R and Y have the definitions of claim 1 to obtain the corresponding immonium salt of claim 1. 

1. IMMONIUM SALTS OF THE FORMULA
 2. The compounds of claim 1 wherein X is chlorinE.
 3. A compound of claim 2 wherein R and R1 are methyl, R2 and R3 together are -(CH2)4- and Y is 1-pyrrolidinyl.
 4. A compound of claim 2 wherein R and R1 together are
 5. A compound of claim 2 wherein R and R1 are methyl, R2 and R3 together are -(CH2)3- and Y is 1-pyrrolidinyl.
 6. A compound of claim 2 wherein R is benzyl, R1 is methyl, R2 and R3 together are -(CH2)3- and Y is 1-pyrrolidinyl.
 7. A compound of claim 2 wherein R and R1 are methyl, R2 and R3 together are
 8. A compound of claim 2 wherein R and R1 are methyl, R2 is phenyl, R3 is hydrogen and Y is 1-pyrrolidinyl.
 9. A compound of claim 2 wherein R and R1 together are -(CH2)2-O-(CH2)2-, R2 and R3 together are -(CH2)4- and Y is morpholino.
 10. A compound of claim 2 wherein R and R1 are methyl, R2 is hydrogen, R3 is tert.-butyl and Y is dimethylamino.
 11. A compound of claim 2 wherein R and R1 are methyl, R2 and R3 together are
 12. A process for the preparation of a compound of claim 1 comprising reacting a phosgene-immonium salt of the formula 